The mission for the Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype project is to determine the complex interaction between chromosomal sex and the major risk factors for late onset Alzheimer?s (LOAD): age, APOE*4 genotype and maternal history of AD. As LOAD accounts for the greatest incidence and prevalence of the disease, determining molecular mechanisms relevant to LOAD has the potential for greatest impact. Further, targeting early stage transitions of risk have the greatest potential for therapeutic efficacy. Thus, research proposed herein focuses on the prodromal / preclinical stage of LOAD and the sex differences that underlie early risks of LOAD progression. Elucidation of sex differences in the mechanisms driving prodromal LOAD will lead to identification of therapeutic targets to change the trajectory of the disease to prevent, delay and potentially reverse course of developing LOAD. To achieve this goal, we have assembled an integrative research team with expertise spanning sex differences in: human brain imaging endophenotypes that emerge during pre-clinical / prodromal phase of LOAD, molecular mechanisms of complex interactions across sex, age, ApoE and mitochondrial bioenergetics and innovative translational AD animal model development, data science and computational systems biology bioinformatics to identify sex specific endophenotypes and therapeutic targets for precision health, Our proposed program of research is organized and integrated across three specific aims designed to determine the complex mechanisms and pathways underlying sex differences in the prodromal LOAD endophenotype. Translationally, we have anchored our approach in the complex biology of humans and integrated that complexity into an innovative animal model that combine LOAD risk factors of age, sex, APOE*4 genotype and maternal mitochondrial DNA inheritance. Aim 1 will establish sex differences in brain prodromal endophenotype using brain PET and MRI imaging in parallel with innovative 31P-MRS imaging of mitochondrial function in human brain. Aim 2 is designed to mechanistically determine the systems biology pathways and networks that emerge during the prodromal phase of LOAD. With UI-JAX Model-AD, we will develop a novel and translationally valid model of LOAD that addresses each of the 4 LOAD risk factors including maternal inheritance of AD through inheritance of the maternal mitochondrial genome and bioenergetic capacity (LOADm4: aged mtDNA-hAPP-hAPOEe4). In Aim 3, multi-scale data from Aims 1 and 2 will be analyzed using an innovative and sensitive computational systems biology approach to detect sex differences in the prodromal transition state of LOAD risk and therapeutic targets to mitigate risk. Outcomes of our analyses will elucidate molecular mechanisms that emerge in midlife and that increase risk of developing AD later in life. Collectively, these data will provide therapeutic targets for sex-based precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest. Research proposed herein address goals of the National Alzheimer's Project Act (NAPA) to prevent and effectively treat AD by 2025 and the NIA Alzheimer's Disease Research Summit 2015 key objectives of sex and metabolic determinants of AD.